Role of proBDNF and p75NTR in HIV-mediated axonal/dendritic degeneration

描述(申请人提供)：人类免疫缺陷病毒-1(HIV)感染中枢神经系统可能会导致一种神经综合征，称为HIV相关神经认知障碍(HAND)。Hand包括轻微的神经认知障碍和一种更严重的运动和认知障碍，称为艾滋病毒相关性痴呆(HAD)。虽然使用高效抗逆转录病毒药物治疗降低了大脑中艾滋病毒的负荷，但由于寿命延长，手部疾病的患病率实际上增加了。因此，必须开发辅助和联合治疗来预防或逆转在这些个体中观察到的神经缺陷。这些受试者表现出突触简化和神经元凋亡。然而，导致突触病理的分子机制尚不清楚。开发有效治疗方法的关键是更好地了解病毒导致这些神经病理特征的分子和细胞机制。HIV及其病毒包膜蛋白gp120促进轴突回缩和树突简化。这些效应是由前神经营养因子脑源性神经营养因子(ProBDNF)复制的，并由肿瘤坏死因子家族成员p75神经营养因子受体(P75NTR)介导。因此，我们提出了这样的假设，即proBDNF通过促进p75NTR的激活而促进HIV的神经毒性。我们已经获得了支持这一假设的初步数据。事实上，我们已经表明，HAD受试者的大脑显示出比非HAD受试者更高数量的proBDNF。此外，体外数据已经确定，p75NTR拮抗剂可以阻断HIV和gp120介导的突触树突简化。因此，这一提议将检验这一新的假设，即HIV通过gp120介导的机制损伤神经元，该机制涉及proBDNF的释放，而proBDNF又通过p75NTR介导的机制促进轴突/树突变性。将进行实验，以确定p75NTR在HIV/gp120介导的神经毒性中的作用，以及HIV/gp120促进proBDNF积累的细胞机制。这些措施包括测试将proBDNF加工成成熟BDNF所涉及的酶的活性。这些实验将伴随着在死后人脑和HAD动物模型中检测参与proBDNF处理的蛋白水解酶的研究。还计划进行研究，以确定proBDNF与小胶质细胞激活和炎症之间的关系(如果有的话)。我们期望就p75NTR在HIV神经毒性中的作用提供新的有意义的数据。这些数据将有助于设计p75NTR拮抗剂作为对抗艾滋病毒引起的突触简化的辅助疗法。

DESCRIPTION (provided by applicant): Human Immunodeficiency Virus-1 (HIV) infection of the central nervous system may cause a neurological syndrome termed HIV-associated neurocognitive disorders (HAND). HAND includes minor neurocognitive disorders and a more severe form of motor and cognitive impairments termed HIV associated dementia (HAD). Although treatment with highly active antiretroviral agents decreases the load of HIV in the brain, the prevalence of HAND is actually increased due to longer life. Therefore, adjunctive and combined therapies must be developed to prevent and perhaps reverse the neurologic deficits observed in these individuals. These subjects exhibit synaptic simplification and neuronal apoptosis. However, the molecular mechanisms leading to synaptic pathology are unknown. Key to developing effective therapies is a better understanding of the molecular and cellular mechanisms by which the virus causes these neuropathological features. HIV and its viral envelope protein gp120 promote axonal retraction and dendritic simplification. These effects are reproduced by the proneurotrophin brain-derived neurotrophic factor (proBDNF) and are mediated by the p75 neurotrophin receptor (p75NTR), a member of the tumor necrosis factor family. Thus, we have generated the hypothesis that proBDNF facilitates HIV neurotoxicity by promoting the activation of p75NTR. We have obtained preliminary data in support to this hypothesis. Indeed, we have shown that brains of HAD subjects exhibit a higher amount of proBDNF than non-HAD subjects. Moreover, in vitro data have determined that HIV and gp120-mediated synaptodendritic simplification is blocked by p75NTR antagonists. Thus, this proposal will test the novel hypothesis that HIV injures neurons by a gp120-mediated mechanism that involves the release of proBDNF, which in turn promotes axonal/dendritic degeneration via a p75NTR-mediated mechanism. Experiments will be carried out to establish the role of p75NTR in HIV/gp120 mediated neurotoxicity, and the cellular mechanisms whereby HIV/gp120 promotes proBDNF accumulation. These include testing the activity of enzymes involved in processing proBDNF to mature BDNF. These experiments will be accompanied by studies examining proteolytic enzymes involved in proBDNF processing in postmortem human brain as well as in animal models of HAD. Studies are also planned to establish the relationship (if any) between proBDNF and microglia activation and inflammation. We expect to provide new significant data on the role of p75NTR in HIV neurotoxicity. These data will help in the design of p75NTR antagonists as an adjunct therapy against synaptic simplification caused by HIV.